This invention relates generally to the compound 2,4-diaminopyridine (2,4-DAP), and more particularly to a method for using 2,4-DAP as an antagonist of certain muscle relaxants used during surgical operations and for the enhancement of neuromuscular transmission in certain disease states.
A number of muscle relaxants, typified by curare, find wide use in medicine and surgery. Curare, originally used as a poison for arrow tips by South American Indians, is routinely administered by anesthesiologists preparing patients for surgery. Curare acts as a muscle relaxant by decreasing neuromuscular transmission, thereby inducing paralysis at high dosages.
There is a corresponding need in anesthesiology for agents to reverse the effects of clinical muscle relaxants, preferably by facilitating or enhancing neuromuscular transmission. Moreover, such agents are potentially useful in the treatment of diseases which cause decreased neuromuscular transmission, such as botulism and myasthenia gravis, and as a reversal agent for certain antibiotics having a neuromuscular blocking action.
One compound that has been shown to be clinically useful in this regard is 4-aminopyridine (4-AP). ##STR1##
4-aminopyridine has been clinically used for several years, particularly in Bulgaria, as an antagonist of the action of some muscle relaxants used in anesthesiology. (Paskov et al., Eksp. Khir Anaestesiol. 18, 48-52 (1973)). In addition it has been shown that 4-AP potentiates anticholinesterase drugs (e.g. neostigmine and pyridostigmine) in their antagonistic action against neuromuscular blocking drugs used in surgery (Miller et al., Anesthesiology 50, 416-420 (1979)).
4-AP exerts a potassium channel blocking action in axonal membranes, prolonging nerve action potentials. This effect leads to an enhanced calcium ion influx and an increased release of neurotransmitters. Additionally, 4-AP has been used to reverse the neuromuscular block of several antibiotics, in the treatment of myasthenia gravis, the Eaton Lambert syndrome, botulism, Huntington's chorea, and even multiple sclerosis. It also antagonizes morphine-induced respiratory depression and ketamine-diazepam anesthesia.
Nevertheless, despite its continuing clinical use, 4-AP has a number of undesirable effects that limit its clinical usefulness. These effects stem from its central nervous system action. 4-AP causes enhanced autonomic and central transmission, leading, inter alia, to hypertension and convulsions at dosage levels only slightly exceeding the clinical dosage.
Some early experimental work has now been done with 3,4-diaminopyridine (3,4-DAP). ##STR2##
This compound exhibits stronger peripheral action and less central action than 4-AP in vitro, most likely because it has more difficulty passing the blood-brain barrier. However, in vivo, the action of 4-AP and 3,4-DAP were almost the same (Durant, et al., Eur. J. Pharmacol. 84, 215-219 (1982)). Moreover, the LD.sub.50 values for intraperotoneal 4-AP and 3,4-DAP in mice are 10 mg./kg. and 20 mg./kg., respectively (Vohra, et al. J. Med. Chem 8, 296-304 (1965)). The LD.sub.50 dosage corresponds to a lethal dose in 50% of the animals treated. Thus, although not as toxic as 4-AP, 3,4-DAP suffers from the similar disadvantage of high toxicity at dosage levels near those that would be used in therapy. Like 4-AP, possible beneficial effects of 3,4-DAP at relatively high dosage levels cannot be explored because of its tendency to cause convulsions before such levels are reached.
Accordingly, there is a need for a muscle relaxant antagonist that has enhanced peripheral activity, less central action, and lower toxicity than 4-AP.
Therefore, it is an object of the invention to provide a method for antagonizing the actions of certain muscle relaxants resulting in enhanced peripheral activity and decreased central action. Another object of the invention is to provide a pharmaceutical composition containing an active muscle relaxant antagonist that is less toxic than 4-AP and 3,4-DAP.